In a recent study posted to bioRxiv*, researchers in the United States assessed the impact of metabolic diseases on coronavirus disease 2019 (COVID-19) vaccine immunogenicity in a mouse model.

The proportion of individuals with diabetes mellitus (DM) and obesity is increasing globally, particularly among high-income countries. Obesity, DM, advanced age, male sex, and other comorbidities are recognized risk factors for severe COVID-19 and death. Many COVID-19 vaccines are less effective in diabetic/obese individuals.

Clinical studies observed that type 2 DM (T2DM) is linked to the attenuation of immune responses following COVID-19 mRNA vaccination. Moreover, poor vaccine immunogenicity has been noted in adults with obesity, suggesting that metabolic diseases influence vaccine responses. Still, the exact effects on the quality of cellular and humoral responses are unclear. 

Study: Reduced SARS-CoV-2 mRNA vaccine immunogenicity and protection in mice with diet-induced obesity and insulin resistance. Image Credit: Leremy / Shutterstock

The study and findings

In the present study, researchers evaluated the effects of T2DM and obesity on antibody functions, T-cell responses, and protection from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) challenge in mice immunized with the BNT162b2 vaccine. First, they established an obese, hyperinsulinemic, hyperglycemic, and glucose-intolerant murine model by feeding C57BL/6J mice a high-fat diet (HFD). In parallel, control mice were fed a normal diet (ND).

Later, these HFD- or ND-fed animals were immunized with a two-dose regimen of BNT162b2 mRNA or a protein subunit vaccine (alum-adjuvanted recombinant SARS-CoV-2 spike receptor-binding domain [RBD]). BNT162b2 vaccine induced robust humoral responses, while the subunit vaccine elicited limited antibody responses in ND-fed mice. In addition, HFD-fed BNT162b2-immunized mice showed a 2.2-fold reduction in anti-spike immunoglobulin G (IgG) than their ND-fed counterparts.

Next, the researchers evaluated the neutralization potency of immune sera in surrogate and live-virus neutralization tests. HFD-fed mice exhibited significantly attenuated neutralizing potency relative to ND-fed mice following BNT162b2 vaccination. Further, they evaluated the correlations between weight at immunization or fasting insulin and antibody responses in HFD-fed mice and found that serum insulin levels negatively correlated with anti-spike IgG titers.

Splenocytes were harvested and stimulated with overlapping spike RBD peptides. ND-fed mice immunized with the BNT162b2 vaccine showed higher levels of T cell-expressed interferon (IFN)-γ, tumor necrosis factor (TNF), and interleukin (IL)-2 than ND mice injected with phosphate-buffered saline (PBS).

In contrast, BNT162b2 vaccination caused no significant induction of these cytokines compared to PBS administration in HFD mice. In addition, ND-fed mice exhibited a minimum of two-fold higher median cytokine levels than HFD-fed mice. Finally, immunized mice were intranasally challenged with 10³ plaque-forming units (PFU) of live mouse-adapted SARS-CoV-2.

Body weight was determined before infecting the animals. HFD-fed mice were significantly heavier than ND-fed mice. Animals were euthanized two days post-infection, and their lungs were harvested. There was evidence of minor inflammation in all lung specimens. The expression of chemokines, cytokines, and IFN-stimulated genes in the lungs was determined.

ND- and HFD-fed mice injected with PBS showed high inflammatory responses across several genes. Notably, ND mice immunized with the BNT162b2 vaccine had lower gene expression than PBS-administered mice. However, there were no significant differences between BNT162b2- and PBS-administered HFD mice.

PBS-administered HFD and ND mice showed high viral load in the lungs. Mice immunized with the protein subunit vaccine were not protected from infection. BNT162b2-immunized ND mice showed significant declines in lung viral titers relative to their PBS-administered counterparts. Contrastingly, HFD-fed mice receiving BNT162b2 or PBS showed no significant differences in lung viral titers.

ND-fed mice immunized with the BNT162b2 vaccine had 262-fold lower lung viral titers than HFD-fed mice, albeit the difference was statistically insignificant. The authors observed that neutralizing titers were inversely correlated with lung viral titers and the expression levels of IFN-induced protein with tetratricopeptide repeats 2 (Ifit2).

Conclusions

In summary, the researchers illustrated that HFD-induced obesity and insulin resistance impair humoral and cellular immune responses following two-dose BNT162b2 vaccination. HFD-fed mice had marked reductions in immune responses than ND-fed mice. Further, ND-fed mice showed potent RBD-specific T-cell induction, which was absent in HFD-fed mice.

Of note, HFD-fed mice receiving the BNT162b2 vaccine lacked protection against live SARS-CoV-2 challenge, whereas ND mice were relatively protected. The study’s limitations include using only male animals, and the magnitude of T-cell responses was low due to using an RBD peptide pool instead of full-length spike peptides. Overall, these findings corroborate the need for precision SARS-CoV-2 vaccines for those with diabetes and obesity.

*Important notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information

Written by

Tarun Sai Lomte

Tarun is a writer based in Hyderabad, India. He has a Master’s degree in Biotechnology from the University of Hyderabad and is enthusiastic about scientific research. He enjoys reading research papers and literature reviews and is passionate about writing.